Prognosis

In general, the prognosis of RDD is good and nodal-limited disease typically has a benign course [1, 20, 34]. When RDD is extranodal and involving multiple systems, prognosis may be more guarded, although longitudinal studies are lacking [1, 34].

Conclusions

The histiocytic neoplasms that involve the lung are very rare diseases that can be a source of significant morbidity and mortality. The recent discoveries of mutations in the

MAPK pathways have offered important insight into disease pathogenesis, allowing for the reclassification of histiocytic syndromes as inflammatory monomyelocytic neoplasms. The disease-driving mutant cells of the histiocytic syndromes appear to be most consistent with immature myeloid precursors with arrested development due to mutations that occur at different nodes in the RAS/ MAPK/MEK/ERK and PI3K pathways. The identification of targetable mutations in PLCH, ECD, and RDD offers exciting new therapeutic options and genetic testing is now a key step in the evaluation of patients with these diseases.

Diagnostic Criteria for Primary Histiocytic Disorders of the Lung

(Adapted from NCCN Guidelines [22])

PLCH

•\ Even in the setting of highly suggestive clinical/radiological features, biopsy strongly recommended to con rm the diagnosis and to establish the mutational status

––Histology showing histiocytes with grooved nuclei, eosinophilia

––Immunohistochemistry reveals CD1a+, CD207 (Langerin)+, BRAF V600E(VE1)+/−

––Electron microscopy reveals Birbeck granules

––Genetic analysis may be useful in patients when pharmacotherapy is considered

No mutation identi ed BRAFV600E mutation Other MAPK gene mutation

––Vigilance

VE1 IHC positivity should be con rmed with a second molecular assay

Negative BRAFV600E mutational testing should be con rmed with a second genetic modality or biopsy from more than one site

•\ Other recommended studies, as appropriate

––Chest CT

––Pulmonary function testing

––Bone imaging if pain present

––Echocardiogram/right heart catheterization

––Endocrine studies for pituitary involvement

––MRI brain/pituitary/sella turcica

ECD

•\ Even in the setting of highly suggestive clinical/radiological features, biopsy strongly recommended to con rm the diagnosis and to establish the mutational status

––Histology reveals foamy histiocytes, giant cells, lymphoplasmacytic in ltrate

––Immunohistochemistry reveals CD68+, CD163+, S100+/−, factor XIIIa+, CD1a−, Langerin−, BRAF (VE1) V600E+/−

––Genetic analysis reveals

No mutation identi ed BRAFV600E mutation Other MAPK gene mutation

•\ Vigilance is required for atypical presentation

––ECD can occur in the absence of bone disease

––Characteristic xanthomatous histiocytes may be absent

––VE1 IHC positivity should be con rmed with a second molecular assay

––Negative BRAFV600E mutational testing should be con rmed with a second genetic modality or biopsy from more than one site

•\ Other recommended studies

––Chest CT

––Pulmonary function testing

––Bone imaging

––Whole body PET/CT including distal extremities

––CBC, complete metabolic pro le

––Bone marrow aspiration/biopsy

––Echocardiogram/right heart catheterization

––Endocrine studies for pituitary involvement

––MRI brain/pituitary/spine/sella turcica with contrast

––CT sinuses with contrast

RDD

•\ Biopsy strongly recommended

––Histology reveals histiocytes with round nuclei, central nucleoli, emperipolesis, plasmacytosis

––Immunohistochemistry reveals S100+, CD68+, CD163+, cyclin D1+/−, CD1a−, Langerin−

•\ Other recommended studies, as appropriate

––HRCT

––Whole body PET/CT

––CT sinuses, MRI orbit/brain/spine

––CBC with differential

––ALPS panel, ANA, RF, HLA-B27, IgG

––Pulmonary function tests

––Evaluation for anemia if present

––NGS of lesional tissue for MAPK pathway mutations

––If familial RDD is suspected, obtain SLC29A3

––Bone marrow aspiration/biopsy should be considered

Acknowledgments  We thank Ava Borchers for assistance with Fig. 16.1 graphics.

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